Homeobox protein Nkx-2.5

NK2 homeobox 5
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3RKQ​
Identifiers
Symbols	NKX2-5 ; CHNG5; CSX; CSX1; HLHS2; NKX2.5; NKX2E; NKX4-1; VSD3
External IDs	OMIM: 600584 MGI: 97350 HomoloGene: 3230 GeneCards: NKX2-5 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • RNA polymerase II transcription cofactor activity • transcriptional activator activity, RNA polymerase II transcription factor binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • DNA binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • protein binding • transcription factor binding • serum response element binding • protein homodimerization activity • sequence-specific DNA binding • transcription regulatory region DNA binding • protein heterodimerization activity Cellular component • nucleus • transcription factor complex • cytoplasm • RNA polymerase II transcription factor complex Biological process • negative regulation of transcription from RNA polymerase II promoter • vasculogenesis • heart looping • heart morphogenesis • outflow tract septum morphogenesis • cardiac conduction system development • bundle of His development • Purkinje myocyte differentiation • cardiac ventricle formation • right ventricular cardiac muscle tissue morphogenesis • ventricular trabecula myocardium morphogenesis • apoptotic process involved in heart morphogenesis • septum secundum development • proepicardium development • pulmonary myocardium development • transcription from RNA polymerase II promoter • adult heart development • positive regulation of cell proliferation • negative regulation of cardiac muscle cell apoptotic process • positive regulation of transcription via serum response element binding • positive regulation of sodium ion transport • negative regulation of myotube differentiation • hemopoiesis • cell differentiation • BMP signaling pathway • thyroid gland development • embryonic heart tube development • negative regulation of apoptotic process • sarcomere organization • positive regulation of neuron differentiation • positive regulation of heart contraction • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • spleen development • positive regulation of cardioblast differentiation • ventricular cardiac myofibril assembly • cardiac muscle cell differentiation • cardiac muscle tissue morphogenesis • atrial cardiac muscle cell development • ventricular cardiac muscle cell development • regulation of cardiac muscle contraction • pharyngeal system development • cardiac muscle cell proliferation • regulation of cardiac muscle cell proliferation • cardiac muscle contraction • canonical Wnt signaling pathway • positive regulation of transcription initiation from RNA polymerase II promoter • heart trabecula formation • ventricular septum morphogenesis • atrial septum morphogenesis • atrioventricular node cell development • atrioventricular node cell fate commitment • embryonic heart tube left/right pattern formation • negative regulation of canonical Wnt signaling pathway • positive regulation of voltage-gated calcium channel activity • regulation of cardiac conduction Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1482	18091
Ensembl	ENSG00000183072	ENSMUSG00000015579
UniProt	P52952	P42582
RefSeq (mRNA)	NM_001166175	NM_008700
RefSeq (protein)	NP_001159647	NP_032726
Location (UCSC)	Chr 5: 173.23 – 173.24 Mb	Chr 17: 26.84 – 26.84 Mb
PubMed search

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2.5 gene.^[1][2][3]

Function

Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development (Shiojima et al., 1995). It has been demonstrated that a Drosophila homeobox-containing gene called 'tinman' is expressed in the developing dorsal vessel and in the equivalent of the vertebrate heart. Mutations in tinman result in loss of heart formation in the embryo, suggesting that tinman is essential for Drosophila heart formation. Furthermore, abundant expression of Csx, the presumptive mouse homolog of tinman, is observed only in the heart from the time of cardiac differentiation. CSX, the human homolog of murine Csx, has a homeodomain sequence identical to that of Csx and is expressed only in the heart, again suggesting that CSX plays an important role in human heart formation.^[3] In humans, proper NKX2-5 expression is essential for the development of atrial, ventricular, and conotruncal septation, atrioventricular (AV) valve formation, and maintenance of AV conduction. Mutations in expression are associated with congenital heart disease (CHD) and related ailments. Patients with NKX2-5 mutations commonly present AV conduction block and atrial septal defects (ASD). Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. Nkx-2.5 transcription factor may help myocytes endure cytotoxic stress, even though further exploration in this field is required.^[4]

Interactions

During embryogenesis, NKX2-5 is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. In early cardiogenesis, cardiac precursor cells from the cardiac crescent congregate along the ventral midline of the developing embryo and form the linear heart tube. In Nkx2-5 knock out mice, cardiac development halts at the linear heart tube stage and looping morphogenesis disrupted.

NKX2.5 has been shown to interact with GATA4^[5][6][7] and TBX5.^[5][8] NKX 2.5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.^[9] NKX2.5 is dependent upon the JAK-STAT pathway^[10] and works along with MEF2, HAND1, and HAND2 transcription factors to direct heart looping during early heart development. NKX2.5 in vertebrates is equivalent to the ‘tinman’ gene in Drosophila and directly activates the MEF2 gene to control cardiomyocyte differentiation. NKX2.5 operates in a positive feedback loop with GATA transcription factors to regulate cardiomyocyte formation. NKX2.5 influences HAND1 and HAND2 transcription factors that control the essential asymmetrical development of the heart’s ventricles. The gene has been show to play a role in the heart's conduction system, postnatally.^[11] NKX2-5 is also involved in the intrinsic mechanisms that decide ventricle and atrial cellular fate. During ventricular chamber formation, NKX2-5 and NKX2-7 are required to maintain cardiomyocyte cellular identity. Repression of either gene results in the differentiating cardiomyocytes to move towards atrial chamber identity. The Nbx2.5 mutation has also been associated with preeclampsia; though research is still being conducting in this area.^[12]

References

1. Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y (May 1995). "Assignment of cardiac homeobox gene CSX to human chromosome 5q34". Genomics 27 (1): 204–6. doi:10.1006/geno.1995.1027. PMID 7665173.
2. Turbay D, Wechsler SB, Blanchard KM, Izumo S (Jan 1996). "Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx". Molecular Medicine 2 (1): 86–96. PMC: 2230031. PMID 8900537.
3. "Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)".
4. Akazawa H, Komuro I (May 2003). "Roles of cardiac transcription factors in cardiac hypertrophy". Circulation Research 92 (10): 1079–88. doi:10.1161/01.RES.0000072977.86706.23. PMID 12775656.
5. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (Jul 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
6. Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (Sep 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". The EMBO Journal 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC: 1170200. PMID 9312027.
7. Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (Nov 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". The Journal of Biological Chemistry 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
8. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (Jul 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nature Genetics 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
9. Carlson B (2013). Human Embryology and Developmental Biology. Saunders. pp. 104–105; 425.
10. Bodmer R (1993). "The gene tinman is required for specification of the heart and visceral muscles in Drosophila". Development 118 (3): 719–29. PMID 7915669.
11. Winslow R. "In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects". Wall Street Journal.
12. Fugate E. "Developing Genetic Therapies for Congenital Heart Defects". www.muschealth.org.

Further reading

• Harvey RP, Lai D, Elliott D, Biben C, Solloway M, Prall O, Stennard F, Schindeler A, Groves N, Lavulo L, Hyun C, Yeoh T, Costa M, Furtado M, Kirk E (2003). "Homeodomain factor Nkx2-5 in heart development and disease". Cold Spring Harbor Symposia on Quantitative Biology 67: 107–14. doi:10.1101/sqb.2002.67.107. PMID 12858530.
• Chen CY, Schwartz RJ (Nov 1996). "Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription". Molecular and Cellular Biology 16 (11): 6372–84. doi:10.1128/mcb.16.11.6372. PMC: 231639. PMID 8887666.
• Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (Sep 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". The EMBO Journal 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC: 1170200. PMID 9312027.
• Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (Jul 1998). "Congenital heart disease caused by mutations in the transcription factor NKX2-5". Science 281 (5373): 108–11. doi:10.1126/science.281.5373.108. PMID 9651244.
• Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y (Oct 1998). "Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors". The Journal of Biological Chemistry 273 (40): 25875–9. doi:10.1074/jbc.273.40.25875. PMID 9748262.
• Kasahara H, Izumo S (Jan 1999). "Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5". Molecular and Cellular Biology 19 (1): 526–36. doi:10.1128/mcb.19.1.526. PMC: 83910. PMID 9858576.
• Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD (Dec 1999). "Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways". The Journal of Clinical Investigation 104 (11): 1567–73. doi:10.1172/JCI8154. PMC: 409866. PMID 10587520.
• Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S (Jul 2000). "Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease". The Journal of Clinical Investigation 106 (2): 299–308. doi:10.1172/JCI9860. PMC: 314312. PMID 10903346.
• Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (Nov 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". The Journal of Biological Chemistry 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
• Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (Jul 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nature Genetics 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
• Goldmuntz E, Geiger E, Benson DW (Nov 2001). "NKX2.5 mutations in patients with tetralogy of fallot". Circulation 104 (21): 2565–8. doi:10.1161/hc4601.098427. PMID 11714651.
• Toko H, Zhu W, Takimoto E, Shiojima I, Hiroi Y, Zou Y, Oka T, Akazawa H, Mizukami M, Sakamoto M, Terasaki F, Kitaura Y, Takano H, Nagai T, Nagai R, Komuro I (Jul 2002). "Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart". The Journal of Biological Chemistry 277 (27): 24735–43. doi:10.1074/jbc.M107669200. PMID 11889119.
• Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM (May 2002). "Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation". Genes & Development 16 (10): 1234–46. doi:10.1101/gad.222902. PMC: 186286. PMID 12023302.
• Ikeda Y, Hiroi Y, Hosoda T, Utsunomiya T, Matsuo S, Ito T, Inoue J, Sumiyoshi T, Takano H, Nagai R, Komuro I (Jun 2002). "Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease". Circulation Journal 66 (6): 561–3. doi:10.1253/circj.66.561. PMID 12074273.
• Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, Komuro I, Hara J, Miwa T, Yamauchi-Takihara K, Takihara Y (Jul 2002). "The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis". The Journal of Clinical Investigation 110 (2): 177–84. doi:10.1172/JCI14839. PMC: 151044. PMID 12122109.
• Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M, Murray JC (Nov 2002). "Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD". Journal of Medical Genetics 39 (11): 807–11. doi:10.1136/jmg.39.11.807. PMC: 1735007. PMID 12414819.
• Fan C, Liu M, Wang Q (Mar 2003). "Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome". The Journal of Biological Chemistry 278 (10): 8780–5. doi:10.1074/jbc.M208120200. PMC: 1579789. PMID 12499378.

External links

• NKX2-5 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.